Necroptosis

Regulated necrotic cell death mediated by RIPK1-RIPK3-MLKL signaling.

Overview

Necroptosis is activated when caspase-8 is inhibited. TNF signaling activates RIPK1, which recruits RIPK3. RIPK3 phosphorylates MLKL, causing membrane pore formation and release of DAMPs that trigger inflammation.

Cellular Location

Cytoplasm → plasma membrane

Clinical Significance

Alternative cell death when apoptosis is blocked; contributes to ischemia-reperfusion injury; RIPK1 inhibitors in clinical trials.

Key Molecules

RIPK1 RIPK3 MLKL TNF/TNFR1 cIAP1/2 DAMPs (HMGB1, ATP)

Key Enzymes

RIPK1 kinase RIPK3 kinase MLKL (pseudokinase/effector)Caspase-8

Related Pathways

Extrinsic Apoptosis (Death Receptor)

Cell death initiated by death ligand-receptor interactions at the cell surface.

NF-κB Pathway

Master regulator of inflammation, immunity, and cell survival.

Inflammasome Pathway

Intracellular sensor complexes activating inflammatory caspases and IL-1β/IL-18.